<img height="1" width="1" src="https://www.facebook.com/tr?id=1582471781774081&amp;ev=PageView &amp;noscript=1">
  • Menu
  • crown-logo-symbol-1-400x551

Find it Quickly

Get Started

Select the option that best describes what you are looking for

  • Services
  • Models
  • Scientific Information

Search Here For Services

Click Here to Start Over

Search Here For Models

Click Here to Start Over

Search Here For Scientific Information

Click Here to Start Over

In Vitro

Boost oncology drug discovery with XenoBase®, featuring the largest cell line selection and exclusive 3D organoid models. Benefit from OrganoidXplore™ and OmniScreen™ for rapid, in-depth analysis.

Learn More

In Vivo

Enhance drug development with our validated in vivo models, in vitro/ex vivo assays, and in silico modeling. Tailored solutions to optimize your candidates.

Learn More

Tissue

Experience ISO-certified biobanking quality. Access top biospecimens from a global clinical network, annotated by experts for precise research.

Learn More

Biomarkers and Bioanalysis

Leverage our global labs and 150+ scientists for fast, tailored project execution. Benefit from our expertise, cutting-edge tech, and validated workflows for reliable data outcomes.

Learn More

Data Science and Bioinformatics

Harness your data and discover biomarkers with our top bioinformatics expertise. Maximize data value and gain critical insights to accelerate drug discovery and elevate projects.

Learn More

KRAS

Accelerate innovative cancer treatments with our advanced models and precise drug screening for KRAS mutations, efficiently turning insights into clinical breakthroughs.

Learn More

EGFR

Advance translational pharmacology with our diverse pre-clinical models, robust assays, and data science-driven biomarker analysis, multi-omics, and spatial biology.

Learn More

Drug Resistance

Our suite integrates preclinical solutions, bioanalytical read-outs, and multi-omics to uncover drug resistance markers and expedite discovery with our unique four-step strategy.

Learn More

Patient Tissue

Enhance treatments with our human tumor and mouse models, including xenografts and organoids, for accurate cancer biology representation.

Learn More

Bioinformatics

Apply the most appropriate in silico framework to your pharmacology data or historical datasets to elevate your study design and analysis, and to improve your chances of clinical success.

Learn More

Biomarker Analysis

Integrate advanced statistics into your drug development projects to gain significant biological insight into your therapeutic candidate, with our expert team of bioinformaticians.

Learn More

CRISPR/Cas9

Accelerate your discoveries with our reliable CRISPR solutions. Our global CRISPR licenses cover an integrated drug discovery platform for in vitro and in vivo efficacy studies.

Learn More

Genomics

Rely on our experienced genomics services to deliver high quality, interpretable results using highly sensitive PCR-based, real-time PCR, and NGS technologies and advanced data analytics.

Learn More

In Vitro High Content Imaging

Gain more insights into tumor growth and disease progression by leveraging our 2D and 3D fluorescence optical imaging.

Learn More

Mass Spectrometry-based Proteomics

Next-generation ion mobility mass spectrometry (MS)-based proteomics services available globally to help meet your study needs.

Learn More

Ex Vivo Patient Tissue

Gain better insight into the phenotypic response of your therapeutic candidate in organoids and ex vivo patient tissue.

Learn More

Spatial Multi-Omics Analysis

Certified CRO services with NanoString GeoMx Digital Spatial Profiling.

Learn More

Biomarker Discovery

De-risk your drug development with early identification of candidate biomarkers and utilize our biomarker discovery services to optimize clinical trial design.

Learn More

DMPK Services

Rapidly evaluate your molecule’s pharmaceutical and safety properties with our in vivo drug metabolism and pharmacokinetic (DMPK) services to select the most robust drug formulations.

Learn More

Efficacy Testing

Explore how the novel HuGEMM™ and HuCELL™ platforms can assess the efficacy of your molecule and accelerate your immuno-oncology drug discovery programs.

Learn More

Laboratory Services

Employ cutting-edge multi-omics methods to obtain accurate and comprehensive data for optimal data-based decisions.

Learn More

Pharmacology & Bioanalytical Services

Leverage our suite of structural biology services including, recombinant protein expression and protein crystallography, and target validation services including RNAi.

Learn More

Screens

Find the most appropriate screen to accelerate your drug development: discover in vivo screens with MuScreen™ and in vitro cell line screening with OmniScreen™.

Learn More

Toxicology

Carry out safety pharmacology studies as standalone assessments or embedded within our overall toxicological profiling to assess cardiovascular, metabolic and renal/urinary systems.

Learn More

Our Company

Global CRO in California, USA offering preclinical and translational oncology platforms with high-quality in vivo, in vitro, and ex vivo models.

Learn More

Our Purpose

Learn more about the impact we make through our scientific talent, high-quality standards, and innovation.

Learn More

Our Responsibility

We build a sustainable future by supporting employee growth, fostering leadership, and exceeding customer needs. Our values focus on innovation, social responsibility, and community well-being.

Learn More

Meet Our Leadership Team

We build a sustainable future by fostering leadership, employee growth, and exceeding customer needs with innovation and social responsibility.

Learn More

Scientific Advisory Board

Our Scientific Advisory Board of experts shapes our strategy and ensures top scientific standards in research and development.

Learn More

News & Events

Stay updated with Crown Bioscience's latest news, achievements, and announcements. Check our schedule for upcoming events and plan your visit.

Learn More

Career Opportunities

Join us for a fast-paced career addressing life science needs with innovative technologies. Thrive in a respectful, growth-focused environment.

Learn More

Scientific Publications

Access our latest scientific research and peer-reviewed articles. Discover cutting-edge findings and insights driving innovation and excellence in bioscience.

Learn More

Resources

Discover valuable insights and curated materials to support your R&D efforts. Explore the latest trends, innovations, and expertly curated content in bioscience.

Learn More

Blogs

Explore our blogs for the latest insights, research breakthroughs, and industry trends. Stay educated with expert perspectives and in-depth articles driving innovation in bioscience.

Learn More

  • Platforms
  • Target Solutions
  • Technologies
  • Service Types

The Rising Importance of GITR Agonists as Alternative I/O Candidates for Combination Drug Strategies

roles of GITR and importance of GITR agonists in I/OExplore why glucocorticoid-induced TNFR-related protein (GITR or CD357) agonists are becoming increasingly important as alternative immunotherapy candidates for combination therapies.

What is GITR?

GITR is a well-characterized costimulatory receptor that is a member of the tumor necrosis factor receptor superfamily (TNFRSF). GITR is expressed in hemopoietic and non-hemopoietic cell lineages, e.g. natural killer (NK) cells, B cells, macrophages, dendritic cells, epidermal keratinocytes, and endothelial cells. Activation of GITR is by its ligand GITRL, which is also expressed on many cell types.

GITR’s Role in Immune Function

GITR is a surface molecule expressed on activated CD4 and CD8 T cells and FoxP3+ Treg cells. GITR activation regulates cell survival through MAPK cascades (ERK, JNK, p38 MAPK), and leads to upregulation of Bcl-xL and activation of NF-κB pathways (canonical and non-canonical). GITR’s signaling synergizes with T cell receptor (TCR) signaling and results in a cascade of events in T cells that:

  • Enhances their proliferation
  • Increases IL-2, IFN-γ, and CD25 expression
  • Enhances effector functions
  • Inhibits activation-induced cell death/apoptosis
  • Increases survival and frequency of memory T cells

GITR activation on Tregs is thought to play a major role in the antitumor effects of GITR agonists and GITR ligand therapeutics. Recently, a broader GITR impact on other effector T cells has emerged where long-term GITR activation seems to enhance Treg activity and expand their numbers.

Notably, in tumor immune cell infiltrates, there is higher expression of GITR in Tregs than in effector T cells. It’s also not surprising that, similar to other immune checkpoints, shedding of GITR has been reported.

GITRL is also expressed on various immune cell types, including at high levels in antigen presenting cells, dendritic cells, B cells, and macrophages, and GITRL’s levels have been shown to be induced by IFN-β and LPS.

Overall, in the context of immune function, activation of GITR contributes to maximal CD8+ T cell responses against tumors and pathogens by promoting effector T cell function while inhibiting regulatory T cell (Treg) function.

Over recent years, GITR has been recognized as an important immune checkpoint pathway and has gained significant attention by drug developers who have pursued both preclinical and clinical studies with GITR agonists.

Why Does GITR Matter for Immunotherapy?

Since some patients do not respond to current checkpoint blockade immunotherapies, significant research activity has been directed towards developing novel approaches for targeting alternative immune pathways. The overall goal is to extend the benefits of immunotherapy to a greater number of patients.

GITR is an example of a costimulatory immune checkpoint pathway that has gained significant traction over recent years. For instance, monoclonal antibodies (mAbs) targeting GITR have shown great promise because they enhance CD8+ and CD4+ effector T cell activity while inhibiting/depleting Tregs. GITR also has the footprint of a classic immune checkpoint where agonistic GITR antibodies worsen the immunopathology associated with autoimmunity (e.g. in autoimmune gastritis, collagen-induced arthritis, experimental autoimmune encephalomyelitis, diabetes).

Many preclinical studies have successfully used syngeneic mouse models with a variety of cell lines (e.g. B16-F10 melanoma, CT26 colon carcinoma, MC38 colon adenocarcinoma, and TC1 HPV/cervical cancer model) to show that GITR agonists such as GITR Ligand Fusion Protein (GITRL-FP) induce antitumor activity and enhance the tumor antigen–specific CD8 T cell response. Agonistic antibodies have been shown to inhibit tumor growth as a single agent or in combination with other drugs.

A study has also reported that intra-tumoral injection of the anti-GITR agonistic antibody “DTA-1” showed fewer auto-reactive T cells in the spleen as compared to systemic delivery of the antibody. The authors suggest that intra-tumoral delivery may be a more effective approach to induce an antitumor immunity as compared to systemic delivery of GITR agonistic antibodies.

Additional technologies will certainly continue to help advance GITR agonists, such as functional in vitro screens using reversible T cell dysfunction assays and more human relevant preclinical models, such as PDXs and patient-derived tumor organoids (PDO) populated with characterized immune cells.

Clinical Progress with GITR Agonists

Significant clinical progress has been made with investigational GITR agonists, which generally seem to have acceptable safety profiles. For example, in one recent study MK-4166 (an anti-GITR mAb) was found to be well tolerated, and when combined with pembrolizumab (Keytruda®) an objective response rate of 69% (9/13) was reported. Additional ongoing clinical trials testing GITR agonists in combination with other drugs are also showing great promise, albeit it is important to mention that as a monotherapy we are not aware of any GITR agonists showing clinical efficacy.

A recent report of GITR expression across multiple tumor types indicates that some cancer types express GITR on malignant cells including 6% of breast cancers, 5.7% of bladder cancers, 4.5% of primary (but not metastatic) melanomas, and 3.2% of ovarian cancers. The investigators suggest that GITR expression on these tumors may signal towards a new tumor immune evasion strategy that should be explored in additional studies.

Below is a list of investigational GITR agonists (with corresponding clinical trial number and link) that are being tested in combination I/O regimens:

Conclusion

GITR signaling is a strong immune modulator and this pathway is actively being studied in preclinical tumor models and human patients to enhance antitumor responses.

GITR agonists have shown very promising results in tumor growth inhibition, extended survival, and depletion of tumor infiltrating Tregs which was thought to be the primary mechanism of action. However, more recent studies indicate that GITR signaling impacts multiple immune cell subsets including CD8+/CD4+ T cells, antigen presenting cells, and NK cells. In addition, there is emerging data on bidirectional signaling of GITR engagement which likely implicates even more complex pathways.

To fully exploit preclinical studies using GITR agonists, research programs should include multiple in vitro and animal models to best characterize GITR agonists whether anti-GITR agonistic antibodies, GITRL, or GITRL-FP.


Related Posts